PT90308B - PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS CONTAINING AZELASTIN WITH CONTROLLED LIBERTACAOUS ACTIVE SUBSTANCE - Google Patents

Abstract

Azelastine-containing pharmaceutical compositions with controlled release of active substance using a release-delaying component, there being 0.001 to 800 parts of release-delaying component for one part by weight of azelastine (as base), and it also being possible for the azelastine to be in the form of its physiologically tolerated salts, and the rate of azelastine release being between 0.05 and 5 mg per hour.

Description

description

Azelastine is a phthalazinone derivative with the following structural formula:

Cl

CH

your. chemical name is: 4- (4-chlorobenzyl) -2-perhydro-1-methylazepine-4-yl) -1- (2H) -phthalazinone. Azelastine. it is mainly used for asthma prophylaxis. Azelasitin also has anti-allergic and anti-histamine properties, see German patent 2 164 054. i ί i

One of the essential drawbacks in using azelastine is tiredness as a side action. I Many patients also complain of drowsiness, dizziness and similar symptoms. It is especially in the early days of using azelastine that these side effects arise, so that the use of motor vehicles and machines by the patients is not possible, as well as the general attention of these patients is greatly reduced. '

It was therefore highly desirable and was also considered an important advance in medicine, to have forms of administration of azelastine that did not present as | collateral action fatigue. j

In the past, to attenuate the collateral action, it was generally proceeded by developing a preparation with the combination of the respective active substance that causes tiredness and; caffeine. In this case, caffeine had the function of antagonizing the 'active sedative property. This process is not, however, applicable with azelastine, as the elimination semiperiods of t 1/2 of azelastine and caffeine differ greatly (t 1/2 is the time during which the level of active substance in i blood serum, without any other addition of active substance decreases from the initial value to half this value): t 1/2; azelastine is 20 h, but t 1/2 of caffeine is only 5 * 5 bL Consequently, what happens with a simultaneous administration of azelastine and caffeine is that after a certain time the effect of caffeine disappears, so the sedative effect of azelastine is felt again. j

The most common artifice then consists in strongly delaying the release of the active substance caffeine in the administration form, so that a period of prolonged action results. This process, however, is associated with the difficulty of achieving a close parallel between the evolution of the level of both active substances in vivo i in the blood. This is not possible due to the large difference in the elimination of values with the techniques that have actualj ^one mind.

p Azelastine has an extraordinarily unpleasant taste, so that, for example in particular in the case of liquid azelastine compositions (for example juices) it is not pleasant or tolerable by patients, especially children. However, according to the present invention, azelastine compositions whose taste is considerably improved are now possible.

The object of the invention is to obtain a pharmaceutical composition with the active substance azelastine, and a process for its preparation, the side effects of azelastine being largely or even completely eliminated.

!

This objective is achieved through a pharmaceutical composition with controlled release of the active substance, containing auxiliary substances and current additives and a delayed component, characterized by the fact that the active substance azelastine, or a physiologically acceptable salt thereof, is released in a controlled manner, being present in an amount of one part by weight of azelastine: referred to the base, for 0.001 to 800 parts by weight of the delayed component, and the release being from 0.05 to 5 mg, for example i0.05 mg to 5 mg or also 0.05 mg to 1 mg of azelastine / hour.

j When azelastine is present in forms

- 3: of a salt, the amount of azelastine previously indicated on the base increases correspondingly to the molecular weight] of the highest salt. The quantity data in this specification i relating to azelastine always refer to the base, and in the case of a salt they are calculated taking into account their highest molecular weight.

~ _Z I object of the invention also includes a 'process for the preparation of a pharmaceutical composition (controlled release of the active substance by incorporating IUMA active substance © m auxiliaries and additives current and a delayed component which is characterized by [] The fact that it is used as an active substance to be released controls, in particular, azelastine or a physiologically acceptable salt thereof: in the proportion of a part by weight of azelastine, referred to the base, to 0.001 to 800 parts by weight of the delayed component , and adjust to a release rate of 0.05 to 5 mg of azelastine per hour.

Secondary claims describe the preferred embodiments of the invention. I; i

I

Surprisingly, it was found that in order to obtain a form of administration of azelastine without any fatigue side action, it was not absolutely necessary to add caffeine - either delayed or not delayed - but it was enough, on the contrary, that olives active ingredient itself was delayed. Therefore, if you join | active substance azelastine in a form of administration that I have read! berte the active substance for a long period of time] (and if betarding of the active substance is accomplished by success) there is no longer, in patients treated with this form of administration, the appearance of can- | bag. This is all the more surprising since it is known that the olefin is a substance with a elimination semiperiod, as mentioned above, of 20 h.

In pharmaceutical technology, until now, the process of retardation has only been applied to substances with short semiperiods, for example at most 10 hours. The delay of an active substance that has a 20 h semiperiod was until now considered in the pharmaceutical technique precisely as a technical error.

It is also surprising, in these forms of realization, that in its application the bitter taste observed up to the present is no longer felt after taking it.

Therefore, forms of pharmaceutical administration with controlled release of the active substance azelastine or its physiologically acceptable salts are the object of the present invention. Suitable salts are, for example, chloride, acetate, maleate, lactate, citrate, tartrate, glutonate or emborate.

Another objective of the invention is a process i

for the preparation of pharmaceutical administration forms with controlled release of the active substance azelastine or physiologically acceptable salts of azelastine.

The determination of the rate of release of azelastine between 0.05 θ 5 µg per hour is carried out in an aqueous solution under test with pH 1.0 and / or pH 6.8. As for this test solution, it is an aqueous solution with the indicated pH values. PH adjustment is carried out by adding acid or by adding a standard buffer substance.

Examples of pharmaceutical administration forms are: delayed tablets, delayed capsules, pellets, juices, implanted, injections, plasters, susper.

aqueous or oily solutions, oily solutions, granules, dragees, | soft gelatin capsules and microcapsules.

The compositions according to the invention can. obtained as follows:

- 5 ~

il2. binding of azelastine to physiologically acceptable cation exchangers. They can be used as cation exchangers of this nature for example:

Acrylic and methacrylic resins with interchangeable protons, acidic groups: COO®, for example Amberlite ^^ IRP-64.

Polystyrene resins with exchangeable Na ⁺ , acid groups: SO ^ ®, for example Amberlite ^^ IBP-69 · ί

|

In the case of ion exchangers these are acid ion exchangers. The maximum proportion azelastine; : ion exchanger is about 1: 1, and the minimum ratio is about one part by weight of the active substance to 800 parts of the ion exchange resin. Preferably, for one part by weight of the active substance, 1 to 400 parts by weight of the ion exchanger, and most preferably 1 to 100 parts by weight of the ion exchanger are used.

i ί

I Azelastine binding is carried out by passing an azelastine solution through an ion exchanger bed in a column, or by suspending the ion exchanger in an azelastine solution, after shaking, filtering and washing. The charged ion exchanger is dried at temperatures up to about 50 ° C. Preferably the charged ion exchanger particles are further provided with a coating, as described for example in U.S. Patent 4 221 77θ · An advantage of the additional coating. nal is to modify and control the release rate of the active substance by choosing the coating material. The drying of the particles of the ion exchanger collected and coated can be carried out with hot air from 70 ° C to 90 ° C.

The ion exchanger particles carry6

das can be packaged in hard gelatin capsules, or a suspension can be prepared as a pharmaceutical administration by means of water, thickeners, flavorings and stabilizers and preservatives.

2nd.

Coating of particles, granules or pelletized grains of the active substance, or of tablets containing azelastiná, with coatings with the following substances, these coating substances may also be used in more. ture: phthalate or hydroxypropylmethylcellulose acetate succinate; cellulose acetate, starch, as well as polyvinyl; carboxymethylcellulose; polyvinylacetate; methylcellulose phthalate, methylcellulose succinate, methylcellulose phthalates, as well as methylcellulose phthalates; teina; ethylcellulose as well as ethyl succinate. cellulose; shellac; gluten; ethylcarboxyethylcellulose; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinylmethyl ether copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate-maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxy4 methyl ethyl cellulose monooctanoate; glycerin; cellulose acetate succinate;

polyarginine anionic fats, oils, waxes, fatty alcohols: methacrylic acid and methacrylate polymer (Eudragit ^)

S); copolymer of acrylates and methacrylates with a low content of ammonium groups (Eudragit ^^ RS) as well as copolymers of acrylates and methacrylates and trimethylammonium methacrylate (EudragitRL), ethyl acrylate and methyl methacrylate copolymers 70:30 (E) 30:30 (E) ,% ro copolymer of acrylic acid, methacrylic acid as well as yours! esters (ratio of free carboxyl groups to ester groups, in example 1: 1) (Eudragit ^ ¹ L 30 D).

The substances mentioned may additionally contain standard plasticizers (eg dibutyl sebacate, citrates and tarts, glycerin and glycerol esters - 7 -

rin, phthalates and the like) and in addition water-soluble substances, such as polyethylene glycols, polyvinyl pyrrolidone, polyvinylpyrrolidone and polyvinylacetate copolymers, hydroxypropylcellulose, hydroxypropylmethylcellulose, may additionally be incorporated. It is also possible to

in the coating.

Pellet grains, granulate grains or tablets may also contain additives of organic acids (such as citric acid, tartaric acid, maleic acid, fumaric acid and ascorbic acid) incorporated.

coating is carried out by spraying solutions in organic solvents or suspensions of the mentioned substances in organic solvents or water, and other auxiliary substances can be added to optimize their characteristics, such as surfactants and pigments.

Spraying is carried out, for example, in dredging boilers or in perforated boilers, or by the air suspension process (for example with a VíLSD 5 turbulent flat layer device) · coating can also be carried out in a mixing process, obtaining the called microcapsules «coating can also be carried out by coagulating aqueous dispersions of the substances mentioned above by mixing the active substance with the dispersion and removing water by drying.

The particles of the coated active substance and the coated granules can be compressed into compressed form and the coated granules can be packaged 8 -

in hard gelatin capsules.

ί In the coating of the substance particles! active substances or granules containing particles of ί actl.va are currently used more coating substances than in the case of pellets, since the surface to be covered is substantially larger than in the case of pellets <> ji

For one part by weight of the active substance, 0.001 to 800 parts by weight of the coating substance i can be used. A weight ratio of one part of the active substance and 0.005 to 500 parts by weight of the coating material is preferable and 0.01 to 200 parts by weight of the coating material per one part by weight of the active substance are especially preferred. The incorporation of the coating substances is carried out at high temperatures, preferably in a draft. The temperature of the inlet air can be i for example 70 to 90 ° θί the temperature of the gas at the end can be j for example up to 40 ° C. I

I

52. Coating of granules, tablets, granules, containing azelastine and one or more substances osmotically i

-active (eg manite or sorbite) with a semi-permeable membrane formed for example from 70 to 90 parts in | weight of cellulose acetate and hydroxypropylmethylcellulose! (50 to 10% by weight).

! ;

ί ί

H As in- osmotically active substances, they also have organic and inorganic compounds or soluble substances that produce an osmotic pressure gradient! with respect to outside liquids through the semi wall; Permeable I. Osmotically active agents or osmotically active compounds comprise magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium hydrogen phosphate, urea, sucrose and the like.

tés »Other osmotically active agents are known from US patents 5/8 770, 4 077 407 ^and A 235 236.

As semipermeable materials that are known as polymers for irreversible osmosis, for example, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, glucan acetate, acetaldehyde-dimethylacetate, cellulose-acetate -ethyl carbamate, polyamide, polyurethane, polystyrene sulfonase, cellulose acetate-phthalate, cellulose acetate-methyl-carbamate, cellulose acetate-succinate, cellulose acetate-dimethylaminoacetate, cellulose acetate-chloroacetate, cellulose dipalmitate, cellulose dioctane , cellulose tipprilate, cellulose dipentanate, cellulose acetate-valerate, cellulose acetate-p-toluenesulfonate, cellulose acetate-butyrate, ethyl cellulose, selectively permeable polymers that are formed by simultaneous precipitation of polycations and a polyanion, such as described in U.S. patents 3 173 876, 3 2/6 586, 3,541,005, 5,541,006 and 3,546,142.

These semipermeable membrane coatings can also be carried out, for example, according to DE-A-331008m and DE-A-331OO96.

The fraction of the osmotically active substance referred to one part by weight of azelastine can range from 10 to 800 parts by weight, preferably from 20 to 500 parts, and most preferably from 50 to 400 parts by weight. The coating substances are applied in such an amount that the semipermeable membrane has a thickness of 50 to 500 µm, preferably 100 to 300 µm.

The incorporation of osmotically active substances can be active substance and can be carried out at room temperature and 80 ° C. For adjusting the release rate, for example, with the help of a laser beam, a hole in the membrane wall is opened so that after introduction

from the tablets thus prepared in an aqueous liquid the active substance is dissolved or suspended by the liquid that penetrates the wall and is expelled through the orifice by the action of pressure.

The application of the semipermeable layer is carried out, for example, at 70-90 ° C air temperature.

The semipermeable membrane may also also contain a microporous layer or, alternatively, microporous substances may be incorporated (see German published patent 3 310 081 in this regard, for example on pages 7 to 17).

The materials that are suitable for the preparation of the microporous layer comprise, for example, polycarbonates of linear polyesters of carbonic acid, in which the carbonate groups alternate in the polymer chain, microporous materials that have been prepared by phosgenation of a dihydroxy aromatic compound, such as bisphenol, of a microporous polyvinyl chloride, microporous polyamides such as non-adipoamide polyhexamethyl, acrylic polymers including those formed from polyvinyl and acrylonitrile polychloride, microporous sterin-acryl monomers and their copolymers, porous polysulphones characterized by a linear diphenone , halogenated polyvinyl, polychloroether, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride thereof with an alkylene polyol, polyalkylene sulfides, phenolic polymers, polyesters, microporous poly saccharides with subst anhydroglucose units items that have decreasing permeability for water and biological liquids, asymmetric porous polymers, cross-linked olefinic polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers with a reduced density, as well as products that are described in the specifications.

US-PS 5 595 752, 3 645 178, 3 654 066,

709 774, 3 718 532, 3 80 3 601, 3 8 5 2 224, 3 8 5 2 388 and

853 601; GB-PS 1 126 849 and Chemical Abstracts Vol. 71, 427 ?, 22573? , 1969.

Other microporous materials for the preparation of microporous layers include polyurethanes, elongated cross-linked polyurethanes, polyimides, polygenzi midazois, regenerated collodion, semi-solid cross-linked polyvinylpyrrolidone, microporous materials that have been prepared by diffusion of polyvalent cations in polyelectrolytic solids, microporous derivatives polystyrene such as sodium polystyrene sulfonate, polyvinylbenzyl trimethyl ammonium chloride, microporous cellulose acylate and similar microporous polymers, which are known from the specifications.

US-PS 3,524,752, 3,565,259, 3,276,589, 3,541,055, 3,541,006, 3,546,642, 3,615,024, 3,646,178, and 3,852,224.

The pore-forming agents suitable for the preparation of the microporous layers comprise solid and liquid pore-forming substances. The term 'pore former, as used herein, also encompasses substances that produce micro-openings, and the elimination of pore former may lead to both species. The term pore-forming liquids includes, within the scope of this description, pasty substances and viscous liquids. The pore builders can be organic or inorganic and the polymer forming the layer generally contains 5 to 70% by weight of the pore builder, especially 20 to 50% by weight. The expression pore-forming, for both solids and liquids, comprises substances that can be extracted or eliminated from the precursors of the porous membranes by the liquids existing in the environment of use, with the formation of an effective open cell microporous layer. The pore-forming solids have a

granuometry of approximately 0, 1 to 200 μη and comprising alkaline salts such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate and the like, organic compounds such as saccharides, including saca rose sugars, glucose, fructose, mannite, mannose, galactose, sorbite and the like. Also of interest is the use of soluble polymers such as Carbowaxe, Carbopol and the like. Pore-formers further comprise diols, polyols, polyfunctional alcohols, polyalkylene glycols, polyglycols, ools and the like (OC-db) -alkyl and n-d.

4 ° Incorporation of the active substance azelastine or its binding in the following substances or mixtures of these substances:

- edible fats, for example triglycerides of saturated fatty acid acids θ8 ^ 16θ2 ^to ^ ® ^ 18 ^ 36 ⁹ 2 ^and mixtures thereof, peanut oil and hydrogenated peanut oil, castor oil and hydrogenated castor oil, aseite, sesame oil, cottonseed oil and hydrogenated cottonseed oil corn oil, wheat germ oil, sunflower oil cod liver oil, mixtures of glycerin monoesters, esters and triesters, stearic acid trioleate.

- non-edible fats, for example esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms) with mono-functional aliphatic alcohols (1 to 20 carbon atoms), carna wax bA, beeswax, fatty alcohols (linear or branched) with chain lengths ^up, especially BE ^, / ^ ΐ ΟΗ.

- polymers such as de or palmitic to stearic diacids with glycerin, diglycol stearate substances similar to gordus z ú- 13

poly (vinyl alcohol), polyvinyl chloride, poly (Scido r ÍR) acrylic), (Carbopol ^k anionic acid oolymers

CR) methacrylic and methacrylates (Eudragit ^k 'S), copolymers of acrylates and methacrylates with trimethylammonium (Eudragit ^) RL, Eudragit RS),

Copolymers of ethyl acrylate and methyl methacrylate (EudragitNE JOD) as well as acrylic acid, methacrylic acid and its esters (ratio of free carboxyl groups to ester groups 1: 1) (Eudragit ^ ^J LJOD) polyethylene, poly (glycolic acid ) poly (hydroxybutyric acid), poly (lactic acid) copolymers of lactic acid and glycolic acid (manufacturer: Boehringer Ingelheim) copolymers of lactic acid and ethylene oxide, copolymers of glycolic acids and ethylene oxide, lactic acid copolymers and hydroxybutyric acid, hydroxypropyl phthalate ·· methylcellulose or its acetatesuccinate;

cellulose late, starch acetatophthalide, as well as polyvinyl acetal tophthalate; aarboxymethylcellulose, phthalate, succinate, methylcellulose phthalatesuccinate, methylcellulose phthalic acid hemiester; teina; ethyl cellulose; shellac; gluten; ethylcarboxyethylcellulose; ethyl acrylate-maleic anhydride copolymer; anhydride maleic acid vinyl vinyl ether copolymer; styrene-maleic acid copolymer; 2-ethylfexyl-acrylate-maleic-anhydride; crotonic acid-vinyl acetate polymer; copolymer

glutamic / glutamate; carboxymethylcelluose-glycerin monooctanoate; cellulose acetatesuccinate; polyarginine;

cross-linked alginate; cross-linked gelatin;

thickeners, such as methyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (Pharmacoat, Methoel E = methylcellulose propylene glycol ether), alginic acid and its salts, (sodium or calcium salts, and also sodium alginate mixtures and calcium salts, for example hydrogen phosphate calcium) starches, carboxymethyl starches, carboxymethylcellulose and their salts (eg sodium salt) galactomannan, gum arabic, Karava gum, Ghatti gum. ₍

agar-agar, carrageenan, xanthan gum, guar gum and its derivatives, locust bean flour, noglycol propyl alginate, pectin and tragacanth.

For one part by weight of azelastine, for the delayed components, 1 to 800 parts by weight of the delayed component are used, preferably 1.8 to 600 parts by weight and most especially preferably 2.0 to 400 parts in Weight. The preparation of these compositions is carried out at temperatures between 18 ° C and 80 ° 0o

The preparation of these compositions for administration can take place;

a) By dissolving or dispersing azelastine or a salt thereof in said fats or fat-like substances, or in mixtures thereof, and also by melting the mentioned substances and then cooling them again, crushing them, possibly adding other substances such as for example the substances already mentioned above soluble in water or dispersible in water, and compression in the form of tablets. Cooling of the melt and crushing can also be carried out in the same step, by dispersing the melt in cold water or subjecting it to spray solidification.

In the case of use as retarded agents of the aforementioned oils, azelastine or its salts are dissolved or suspended in oil and eventually, after the addition of up to 2% of aluminum monostearate, it is packed in ampoules and then sterilized or eventually , after addition of the palatable substances and / or sedimentation retardants, such as finely disintegrated silica (for example Aerosil ''), it is homogenized and packaged in bottles »

b) By mixing azelastine with the fats, polymers or thickeners or mixtures of these substances, also using heat, and compresses of

mixture, possibly after the addition of other auxiliary substances, in tablets or the formation of granules,

c) By mixing azelas, ina with solutions of the cold fats or polymers in water or in organic solvents, such as for example ethanol, ethyl acetate, acetone or isopropanol, possibly the mixture with support materials such as cellulose, as well as the subsequent evaporation of the solvent and the mixing of the material containing the active substance thus obtained with other auxiliary substances and their transformation into molded bodies, such as tablets or granules,

d) Wetting a mixture of azelastine and said thickeners with organic solvents, such as ethanol, ethyl acetate, acetone or isopropole, possibly with the incorporation of binders, such as livinylpyrrolidone or copolymers of polyvinylpyrrolidone and livinylacetate, granulation of the obsolete mixture, the subsequent drying, addition of other possible auxiliary substances and molding of the mixture in the form of tablets,

e) By mixing azelastine with a solution of natural or synthetic resin, such as shellac or poly vinylacetate in polyethylene glycol of molecular weight 200 up to 1500, possibly the addition of other auxiliary substances such as stearates or thickeners, and encapsulation of the obtained masses in hard or soft gelatin capsules.

More generally, the pharmaceutical compositions are prepared in a manner known to you, in addition to the delayed components mentioned, known and current pharmaceutical auxiliary substances, as well as other vehicular substances and current diluents, and the auxiliary substances mentioned can also be used. as delayed components they can also perform other functions, for example acting as separating agents or as auxiliary dispersants of this nature,

As vehicular substances and substances substances that are recommended or indicated in the sources of literature mentioned below as auxiliary substances for pharmacy, cosmetics and related fields:

Ullmanns EncyklopãcLie der technischen Che mie, Vol. 4 (1953), p. 1 to 39 5 Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918 et seq., H. v.Czetsch-LincLenwalcl, Hilfsstoffe fíir Pharmazie uncL angrenzencLe Gebiete; Pharm. Ind., Vol. 2, 1961, p. 72 et seq .; Dr. Η. P. Fiedler, Lexikon der Hilfsstoffe fíir Pharmazie, Kosmetik end angrenzende Gebiete, 2nd edition, Editio Cantor, Aulendorf in Wurttemberg 1981.

Examples are auxiliary substances, carrier substances and current diluents to gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starches (for example corn starch) as well as starch derivatives, cyclodextrin and cyclodextrin derivatives, oolivinylpyrrolidone, gelatin, gum. arabic, alginic acid, carboxymethylcellulose, talc, lycopodium, silica (eg colloidal) levulose, tragacanth, sodium chloride, stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially saturated (for example example stearate) polyethylene glycol with an average molecular weight between 200 and 20,000, preferably between 200 and 5,000, especially between 200 and 1000, or mixtures thereof and / or polymers of polyvinylpyrrolidone and / or mixed polymers of vinylpyrrolidone and acetate vinyl, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms) with water monofunctional aliphatic alcohols (1 to 20 carbon atoms) or polyfunctional alcohols such as glycols, glycerin, ethylene glycol, pentaerythrite, sorbite, manite, etc., which may also be esterified, benzyl benzoate, dioxolane, glycerin formal, tetrahydrofluuryl alcohol, polyether glycol ethanol with alcohols having 1 to 12 cLe atoms

bono, dimethylacetamide, lactamides, lactates, ethyl carbonate, silicones (especially polydimethylsiloxane) of medium viscosity) calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, arabic gum, alginic acid, starch, fats and other similar substances.

“In addition to the forms of admission. Pharmaceutical administration may also contain surfactants. Examples include: alkaline soaps, such as alkali salts, in higher fatty acids (eg sodium palmitate or sodium stearate) or their derivatives (eg sodium ricinooleate sulfate); sulfurate or sulphonate compounds, which are formed by reaction of super fatty alcohols. ores with sulfuric acid or chlorosulfonic acid and are used for example as sodium salts (for example sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, sodium cetyl sulfonate); bile acid salts; saponin; quaternary ammonium compounds, partial esters of sorbinate fatty acids;

partial fatty acid esters and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol ether; polyoxyethylene fatty acid esters; ethers of polyoxyethylene fatty alcohols; esters of sucrose fatty acids; esters of polyglycol fatty acids; proteins; lecithin.

Pharmaceutical administration forms may also contain celluloses, especially in the case of tablet preparation. The following types of cellulose are of interest: purified cellulose (for example marketed under the brand name Elcema ^ky ) or microcrystalline cellulose, such as the one that is commercial (R ^- ) used for example with the name Avicel ^ *. Other fillers with binder function may also be used, such as hydr.

calcium genophosphate, lactose, starches (e.g. potato starch, corn starch, modified starches such as ST15OO / / Colorcon starch) glucose, mannite, sucrose.

Pharmaceutical administration forms may additionally contain sedimentation retardants, such as finely dispersed silica, which have a surface area of 50 to 50 m / g, especially 100 to 400 m / g (determined according to the BET method). These substances are commercially available, (R) for example under the brand name Aerosil ^v *.

In addition, the use of release agents in the forms of pharmaceutical administration may be important »In this capacity, mention is made of: siliconised talc, calcium and magnesium stearate, stearic acid, paraffin, hydrated fats, genera and oils, silicone oil emulsions.

As other auxiliary additives, substances that promote breakdown (so-called disintegrants) such as cross-linked polyvinylpyrromidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, formaldehyde may also be of interest. do-gelatin, formaldehyde-casein, poly (acrylic acid) to ultraamyl.pectin »

For the preparation of solutions and suspensions, for example water or physiologically acceptable organic solvents, such as for example ethanol, 1,2-propylene glycol, polyglycols and their derivatives are of interest. For injectable solutions or suspensions, for example, non-toxic solvents or thinners that can be administered parenterally, such as water, 1,5-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, and isotonic saline,

In addition it is also possible to add stabilizers, dyes, anti-oxidants and complexants (for example ethylenediaminetetraacetic acid) and similar substances, as well as the addition of acids such as citric acid, tartaric acid, maleic acid or fumaric acid.

Antioxidants such as sodium metabisulfite, cysteine, ascorbic acid and its flavonoid esters (eg palmitate), gallic acid, alkyl esters of gallic acid, butyllidroxianiso1, nordihidroguaiarético acid, tocoferois, as well as tocopherols + synergists (substances that become bind to heavy metals by complexation, for example lecithin, ascorbic acid, citric acid, or phosphoric acid).

Of interest are preservatives such as sorbic acid, p-hydroxybenzoates (for example, higher alkyl esters), benzoic acid, sodium benzoate, alcohol, trichloroisobutyl, phenol, creol, benzethonium chloride and formalin derivatives.

They are of interest as plasticizers for coating substances; tartar citrates (acetyltriethyl, acetyltributyl, tributyl, triethyl citrate); glycerin and glycerin esters (glycerin diacetate, glycerin triacetate, acetylated monoglycerides and castor oil); phthalates (dibutyl, diamyl, diethyl, dimethyl, dipropyl, 2-methoxyethyl or 2-ethoxyethyl D-phthalate, ethyl and butyl phthalethyl and butyl glycolate); alcohols (propylene glycol, polyethylene glycol of various chain lengths) adipates (of diethyl, di- (2-methoxy- or ethoxy-ethyl); benzophenone; diethyl and dibutyl sebacate, and the respective succinate and tartrate;

diethylene glycol dipropionate; diacetate, dibutyrate, ethylene glycol dipropionate, tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate; sorbitan monoleate.

Solvents from the group of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, ha solvents can be used to incorporate the delayed components or coating substances.

logenates, cycloaliphatic, aromatic, heterocyclic solvents, and their mixtures. Typical solvents include but are not limited to acetone, diacetone-alcohol, methanol, ethanol, propyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n -hexane, n-heptane, ethyl-glycol-monoethyl ether, ethylene glycol monoethyl acetate, methyl chloride, ethylene dichloride, depropylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, cyclohexane, ether, ethoxy cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrophorane, diethylene glycol dimethyl ether, water and mixtures such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol, as well as their mixtures. During the coating process, these solvents are eliminated again. Regardless of the preparation process, the pharmaceutical administration substances according to the invention are characterized by the fact that they release, or allow the release, of the active substance azelastine or its physiologically acceptable salts, with a release rate of between 0, 05 θ 5 per hour, in body fluids.

Dosage indications always refer to azelastine as a base; if azelaszine salts are used, it should be calculated according to the molecular weight.

content of the active substance azelastine in the compositions according to the invention is

a) for administration forms which can be used orally 0.1 mg to 50 mg, preferably 0.2 mg to 50 mg, especially 0.5 mg to 20 mg of the active substance azelastine.

The mentioned individual doses can be applied 1 to 5 times a day, preferably 1 to 5 times, • especially 1 or 2 times,

b) for forms of administration usable by the parenteral route (intravenous, intramuscular, subcutaneous or intraperitoneal): 0.1 mg to 5 mg, preferably 0.2 mg to 400 mg, especially 0.5 to 250 mg of the substance azelastine.

The mentioned individual doses can be administered once a month (for example for subcutaneously applicable implantation) up to 5 times a day, preferably once a month up to 2 times a day, especially once a month up to 1 time a day.

c) For forms of administration that can be used dermally (for example plasters); 5 µg to 5000 mg, preferably 10 mg to 5000 mg, especially 50 mg to 2000 mg of the active substance azelastine.

The individual doses mentioned can be applied once a day to once a month, preferably 1 time every 5 days to 1 time every 5 weeks, especially weekly until every 2 weeks.

The delayed components specially referred to are:

a) sodium poly (styrene, divinylbenzene) cation exchangers (e.g. Amberlite ^^ IBP69). For one part of azelastine (base), for example, 5 to 10 parts of Amberlire '· ^J IHP69 are used.

b) Hyphroxypropyl methylcellulose phthalate coating substances

For a part by weight of azelastine, 1.5 to 5 parts of hydroxypropyl methylcellulose phthalate are used.

Ethylcellulose

For one part of azelastine, 0.1 to 1 parts of ethyl cellulose are used.

Eudragit resins, such as Eudragit RS For one part of azelastine, 0.01 to 0.1 parts of Eudragib ^k '' RS are used.

c) Semi-permeable layers with a core containing osmotically active active substances, and outlet openings: coating with 100 to 300 µm of layer thickness that consists of 82% cellulose acetate to 18% hydroxypropyl methyl cellulose.

d) Substances for incorporating hydrocolloids, for example hydroxypropyl methylcellulose: for one part of azelastine 2 to 10 parts of hydrocolloid. Eudragit ( ^R ) rS;

For one part of azelastine, 10 to 15 parts of Eudragit 'RS.

Glycerin ditripalmitate-esrearate (eg Precirol Act

5)

For one part of azelastine, 1 to 10 parts of Precirol Act 5 ·

The delayed release of the active substance, from 0.05 to 5 P ^or hour, is adjusted to the desired range by the measures recommended in the process claims, in connection with the corresponding indications in the specification. If you want to achieve a release speed within this range, for example, proceed as follows:

12- the preparation of the coating or impregnation of the active substance in the manner described

22_ Substance release test. active, from the form of administration, using the hydrochloric acid 0.1N (2 h) and phosphate buffer pH 6.8 (subsequently) as the release medium.

52- a) If the release proves to be too high: increase in the delayed component fraction and / or reduction in the 23

water-soluble auxiliary substance. Reduction of the fraction of osmotically active substances,

b) if the release proves to be too small;

reducing the fraction of the delayed component and / or increasing the fraction of the water-soluble auxiliary substances.

Increase in the fraction of the osmotically active substance.

In general, a release rate of 1 mg of azelastine per hour is sought.

Example 1;

100 g of azelastine hydrochloride are mixed with 960 g of hydroxypropylmethylcellulose (viscosity of a 2% aqueous solution: 4000 cP (commercial product: for example Methocel K41> Premium)) 1520 g of spray dried lactose and 20 g of stearate magnesium, and the mixture is molded into tablets with a weight of 120 mg, a diameter of 6 mm and a radius of curvature of 6 mm.

Following their preparation, the tablets can be provided, by conventional processes, with a film coating that is soluble in gastric juice or permeable to gastric juice, or resistant to gastric juice.

For the production of a coating resistant to gastric juice 1000 g of tablets are sprayed with about 1000 g of the following suspension, for example in a dredge boiler:

in 480 g of acetone, 65 g of celdlose acetatophthalate are dissolved. This solution incorporates 21 g of diethyl phthalate, 50 S of dichloromethane and 151 g of methanol. In the solution thus obtained, 4.4 g of titanium dioxide are homogeneously suspended.

The spraying is carried out discontinuously _and making dry hot air _supplied between the spraying phases.

One delayed tablet contains% mg of azelastine hydrochloride.

Example 2 g of azelastine hydrochloride, 20 g of Eudragit ^) RS 250 g of talc and 200 g of lactose are mixed together and this mixture is moistened with about 140 g of a mixture formed by 12.7 g of riacetate glycerin (trade name, for example, rriacetin) and 127.3 5 Eudragit R) RS 12.5 · The wet mass is granulated through a 1 mm mesh sieve, as usual, and after drying at temperature environment is nullified in the

CR) dredge a mixture formed by 909 g of Eudragit ^{k 7} RS 12.5 and 91 g of triacetin, by means of a spray gun. The dry granulate thus obtained is molded by compression, without the addition of other auxiliary substances, in biconvex tablets weighing 500 mg and a diameter of 10 mm.

One tablet contains 5 mg .1 azelastine hydrochloride in a delayed composition.

Example 5 g of azelastine hydrochloride are mixed with 100 g of tartaric acid, 250 g of lactose, 10 g of microcrystalline cellulose (Avicel pH 101) and 7 g of hydroxypropyl cellulose (vis-eosity of the solution at 5 ° ^J '> 75 at 150 cos (for example, trademark: Klucel LF)) and this mixture is pasted with 60 g of a 6.25 aqueous solution and hydroxypropylcellulose (viscosity of the 5% aqueous solution '* 75 at 150 cps (for example, trade mark : Kucel LF)).

The wet mass is compressed through one. a hole diameter of 1 mm and rounded in shape and filafraccionados habicom one 3pheronizer disc assi The granules sieved 300 g of the jim fraction of granules are coated in a conventional manner ethylcellulose (polyethylene glycol designation Carbowax 1540) θ® 720 perforated plate with formed ments are current by treatment obtained are dried and cleavage 800 to 1200 with a solution formed by 42.5 g of commercial: Ethocel type N22) and 57.5 S I5OO (commercial name for example Carbowax 1540) θ® 720 g of chloroform by spraying on a turbulent layer apparatus.

They are packed in hard gelatin capsules of size 3 * 50 mg of the coated granules thus obtained.

One hard gelatin capsule contains 4.4 mg of azelastine chlorate in a delayed composition.

Example 4

The preparation of the pharmaceutical administration forms according to the invention is carried out by incorporation in thickeners;

The following substances are mixed: (values in grams)

Formulation N2 1 2 3 Azelasuine hydrochloride 50 50 50 hydroxypropylmethylcellulose (= lie tho c and 1 K41Í) 480 192 96 Lactose 660 948 1044 magnesium stearate 10 10 10

The mixtures are compressed in a tablet press as flat tablets weighing 120 mg and 6 mm in diameter.

The thickness is, mm 3.25 5.15 5.05 fracture strength (li) 47 48 50 (Heberlein fracture strength test)

One tablet contains 5 µg of azelasine hydrochloride.

The release of the active substance in the apparatus of the American pharmacopoeia XXI (dissolution test apparatus 2, solvents: 500 ml of HCl. 0.1 N, rotation speed: 120 rpm) is as follows:

(release values of active substance as a percentage)

Formulation N2

1 2 3 After 5 min. 4 51 50 60 min 20 75 100 120 min 36 96 180 min 55 240 min 74 300 min. 86 360 min 93 Example 5 100 g of hydrochloride azelastine,

tartaric acid, 500 g of lactose and 700 microcrystalline cellulose are mixed together and then a paste is prepared with about 700 g of pu: ja water.

The wet mass is compressed through a perforated sheet with holes of 1 mm in diameter and the forming threads are fractionated and rounded as usual

- 27 tual, by treatment with a Spheronizer disc. The formed granules are dried and sieved.

1000 g of the granules of the dividing fraction 800 to 125 µm are sprayed with a suspension which is prepared as follows;

In 190 g of pure water 0.6 g of polysorbate 80 is dissolved and 40 g of ethyl ditrat are emulsified with this solution.

To the emulsion thus obtained, 800 g of a 30% aqueous dispersion of a copolymer of acrylates and methacrylates with a reduced content of trimethylammonium methacrylate (R) chloride (= Edragit ^{k J} RS 30 D) are added and stirred for about 10 min.

In 860 g of water 109.2 g of talc and 0.2 g of silicone defoamer oil (Simethicone) are suspended <>

This suspension is incorporated with stirring into the dispersion obtained above.

The application of the varnish suspension thus obtained on the granules is carried out in the usual way, for example using a turbulent spray granulator, at an admitted air temperature of 40 to 50 ° C θ with an exhaust gas temperature maximum of 40 ° C. The drying of the granules is carried out under the same conditions.

Spray an amount of the above mentioned cover suspension so that the total weight of the coated granules is 1042 g.

The coated granules are packed in size 3 hard gelatin capsules in doses of 78.1 mg. One hard gelatin capsule contains 5 mg of olive oil hydrochloride

lastina, in the form of a delayed composition. The release of the active substance from a capsule in the American farlacopeia XXI apparatus (dissolution test, apparatus 2, dissolution medium: 500 nl H01 Ο, ΙΙΤ, rotation speed: 120 rpm) is:

after 1 hour 3.0 mg = 60% after 2 hours 4.5 mg = 90%.

The release of the active substance is therefore 3 mg per hour »

Claims (1)

Proceed as described in example 5, with the only difference of spraying the cover suspension described in example p on the granules in an amount sufficient for the total weight of the dried granules to be 112 ⁷ g. The coated granules are then packaged in size 5 hard gelatin capsules in doses of 84.5 mg. One hard gelatin capsule contains 5 mg of azelastine hydrochloride in a delayed composition. The release of the active substance in a capsule, in the apparatus of the American pharmacopoeia XXI (test conditions identical to those of example 5) θ of: after 1 hour 0.25 mg = 5% after 2 hours 0.50 mg = 10% The release of the active substance is therefore 0.25 mg per hour » Example if as described in example 8. in hard gelatine example 6, ca- 29 bad ORIGINAL in an azelastine capsule m then 1 mg of hydrochloride The release of the American pharmacopoeial substance described in example 5) active XXI (conditions of is after years 0.05 hard gelatine count in a delayed composition »of a capsule in the test apparatus identical to The release mg per hour » Example 8 Capsules with 6 mg of azelastine or suspension with 6 mg of azelastine in 5 nil, connected in each case to highly acid cation exchangers » 8.48 g of azelastine hydrochloride are dissolved in 4 l of pure water. ? 71.5 g of styrenesulfonic acid-divinylbenzene copolymer (crosslinking grade 8 v) are suspended in this solution (commercial pipeline: for example Amberlite ^ ⁷ IR 120) and the suspension is stirred for 5 hours. then filtered through a glass fiber cloth and the filter cake thus obtained is washed twice with 300 ml of pure water each time, and much of the Ρθιη washing water is removed by aspiration » 5 g θ-β gelatine (isoelé point ^ _ citric õ - 7, o, molecular weight 25000 - 35θθθ) (pnoduta ouiercir q λ al: & elita ^ki Collagel, Deutsche Gelatinefabriken, Sborbach / / Neckar) is dissolved in a solution of 5 Normal hydrochloric acid in 800 µl of pure water, in a glass beaker »The filter cake obtained above is suspended in this solution and the suspension thus obtained is stirred for 1 hour» Then the suspension is filtered through a cloth glass fiber and the filter cake obtained is washed twice with pure water, with 200 ml each time, ÔAD ORIGINAL and the washing water is removed by aspiration. The filter cake is dried at 60 ° C. The dry product is packaged in size 4 hard gelatin capsules at a rate of 62 mg. A hard gelatin capsule contains 6 mg of azelastine attached to the strongly acid cation exchanger. A juice contains 5 mg of azelastine attached to the ion exchanger in 5 ml, it was prepared as follows: 7.4 kg of pure water are heated to 90 - 95 ° O in it 0.002 kg of propyl 4-hydroxybenzoate-methyl hydroxybenzoate . X the solution after ^ o- -. - .......... and dissolve and 0.01 / kg of 4de cooled to 70 ^v C, dissolve 0.020 kg of hydroxyethylcellulose (average degree of polymerization; 250) and 3.0 kg of sucrose. After cooling to 25 ° C, 3 g of raspberry flavor and 0.2 kg of modified starch (Starch 1550OColorcon) are dissolved by stirring. 124 g of the ion exchanger loaded with dry azelastine are incorporated into this suspension by stirring. The suspension is then complete with pure water up to 11.0 kg (corresponding to 10 1). The release of the active substance from a capsule or 5 ml of the suspension in the American pharmacopoeia apparatus XXI (dissolution test, apparatus 2, medium 500 ml 0.9% sodium chloride, speed of dissolution rotation: 100 rpm) is in : after 1 hour bp% atos 2 hours W% after hours pO% after 4 hours 53% after 5 hours 65% ORIGINAL BAD ^ 300 S O hours 69% after 7 hours 72 7 after 8 hours Ά% O ad. the hour ; the V From . S.0 wool Process for the prep containing the active substance azelastine, with lead: cl · cl · a 7, nl aar-as i saw in the dysiologically salt ai-vivo iarm Ύ ^: · pa. y mg ae.> mvi get involved with your guys' i ne o) o I bad ORIGINAL acceptable, interchangeable color c) if its physiological salt mingles several osmotically active substances or the substance in or an active substance in the d) incorporating the physiologically acceptable substance into the group of digestible fats, not fats. digestible substances or substances of the type of fats, in polymers or thickeners, or to bind them to these substances, and can also be used additionally, in any of the ways indicated above, also other auxiliary substances and current additives. _ z to _ y ~~ - Process for preparing a pharmaceutical composition according to the claims 1 and / or 2, characterize rizaio by the fact that I prepared them? color icerem, for. asylum .tion oral 0 , 1 to 50 mg of the active substance a s and 1 a. s aina, for aoli- hunting parenteral 0.1 to pOO mg to sara the application ro ~ 0 amal p a 3000 m of the active substance » The recueronve claim orioridç.de the will: German Dido submitted on 20 April l ³ 3d under the